 
New Drug Now Available to Treat Multiple Sclerosis
New Drug Now Available to Treat Multiple SclerosisPeople with multiple sclerosis now have a new treatment option to reduce the number of attacks, or relapses, and lower their risk of long-term disability. The Food and Drug Administration has approved Copolymer 1, known commercially as Copaxone, for use in treating MS. It is only the second type of drug to be approved for MS."Copolymer 1 is an entirely different type of medication than the two beta interferon products previously approved for the treatment of MS," says Kenneth P. Johnson, M.D.,chairman of neurology at the University of Maryland Medical Center. Dr. Johnson was the project director of a national study of the new drug at 11 medical centers, including the University of Maryland Medical Center in Baltimore. Dr. Johnson was also a key researcher of beta interferon, known as Betaseron, which became the first FDA-approved drug for MS in 1993. A second beta-interferon drug, Avonex, is also on the market. Pictured: Kenneth P. Johnson, M.D.
With each attack, the body's immune system assaults the nervous system and can cause damage. Over many years, that damage may result in permanent disability. Multiple sclerosis, which affects about 350,000 people in the United States, is the number one cause of disability among young adults age 15 to 45. Reducing the number of relapses also makes a big difference in the quality of life of MS patients. They miss fewer days of work and have less disruption and worry in their daily lives. "We clearly need new options. Because of flu-like symptoms and other side effects, about 20 percent of patients cannot tolerate beta interferons. In addition, up to 35 percent of patients who are on beta interferons may develop antibodies to the drugs within three years that make them ineffective," says Dr. Johnson. Copolymer 1 is a synthetic polypeptide developed at the Weizmann Institute of Science in Israel. Patients self-administer the drug subcutaneously.
-Ellen Beth Levitt
Cholera Shares an Ancient SecretWhen Vibrio cholerae spoke, Dr. Alessio Fasano listened. The microbe that causes cholera showed the University of Maryland School of Medicine professor the underlying mechanism for a promising new technology. It involves oral delivery of drugs not normally absorbed through the intestine, such as insulin and immunoglobulins, common therapies that now must be administered by injection.Dr. Fasano reported on successful initial tests of oral delivery of insulin and immunoglobulins in the March 15, 1997 issue of The Journal of Clinical Investigation.
Pictured: Dr. Alessio Fasano While studying Vibrio cholerae in hopes of developing a cholera vaccine, Fasano discovered a key that unlocks the tight-junction gate, permitting macromolecules to pass through. That key is a secondary toxin produced by the same microorganism that causes cholera. Called Zonula occludens toxin (Zot), it is a protein that modulates the tight junctions in the small intestine, making the cells of the intestinal wall more permeable. Zonula occludens is Latin for tight junctions. In studies in rabbits, Zot caused a 10-fold increase in insulin absorption and a 2- to 6-fold increase in absorption of immunoglobulins in the small intestine. In diabetic rats, Zot administered with oral insulin lowered serum glucose to levels comparable to those obtained with insulin injections. They lived as long on oral insulin as other rats did when it was injected. "What we have here is a powerful natural system that theoretically can be harnessed to deliver biologically active macromolecules," Fasano said. "Zot seems to be an analog of a normal physiologic process. It's not a drug; there's nothing artificial about it." As so often happens in scientific research, Fasano stumbled across Zot while seeking something else entirely. Working to develop a cholera vaccine, researchers at the University of Maryland's Center for Vaccine Development -- where Fasano directs the gastrointestinal pathophysiology lab -- genetically engineered a cholera toxin lacking the bioactive subunit responsible for the severe diarrhea that makes cholera such a killer. They administered it to volunteer research subjects who were infected with Vibrio cholerae. They didn't develop full-blown cholera, but they still had some diarrhea. Something was making the tissues of their intestinal walls more permeable. Something was loosening the tight junctions. Fasano wanted to know what it was. Cholera was never meant to be a human pathogen, the molecular microbiologist explained. It is a swimmer whose ideal environment is a pond. The human intestine is far too warm for Vibrio cholerae; its oxygen-tension level is too low, and its pH (acid/alkali) balance is all wrong. Trapped inside a human body, Vibrio cholerae is doomed. But people sometimes swallow the water in which the cholera bacteria swim. So, to survive, Vibrio cholerae had to find a way to escape its intestinal prison. The cholera toxin it produces dramatically alters the fluid and electrolyte balance of the intestinal lining, allowing much more water than normal to pass through, water to flush Vibrio cholerae back out where it belongs. That's the underlying mechanism of the unrelenting diarrhea that plagues cholera sufferers. Zot is a second protein produced by Vibrio cholerae to make the cells lining the intestines more permeable if the initial onslaught of cholera toxin fails to free the trapped bacteria. "Through Zot, cholera taught us that the gate from the intestines to the blood stream can be opened and closed," Fasano said. "Zot is a molecule that is able to communicate directly with the molecules that make up the cell walls, to get them to do things they normally do only under physiological stimuli." The researcher called it "humbling to realize that we must learn from bacteria, but it is experience, not size, that makes the difference. Vibrio cholerae is a smart pathogen," he said. "It has survived at least 3,000 years, and to survive that long, you have to be very smart. You have to learn to interact with your host, to speak the language of its cells. Vibrio cholerae has a lot to teach us." Zot research has progressed rapidly since Fasano discovered the protein in 1991. He spent three years purifying the molecule and the past year and a half testing it in the laboratory and in animals. He hopes to collaborate with University of Maryland School of Medicine endocrinologists on Phase I clinical trials in human diabetics soon. -Jennifer Donovan Study Shows Triglyceride Poses New Risk for Heart DiseaseTriglyceride, a type of blood fat, must be considered more seriously as a risk factor for heart disease, especially at levels that today are thought to be safe, according to a new study. In an 18-year follow-up of 460 adults, the researchers found that people with triglyceride levels as low as 100 milligrams per deciliter (mg/dl) were more than twice as likely to suffer from future heart disease than those with less triglyceride. Today, levels below 200 mg/dl are thought to be desirable."Previously, nobody thought triglyceride was a major risk factor at these low levels," says Michael Miller, M.D., director of preventive cardiology at the University of Maryland Medical Center in Baltimore and an assistant professor of medicine at the University of Maryland School of Medicine. "We were surprised that in our study, it turned out to be such an important predictor of future heart disease, including heart attack and requiring bypass surgery or angioplasty," says Dr. Miller, who presented the findings at the American Heart Association's 69th Scientific Sessions.
Pictured: Michael Miller, M.D. After adjusting for other risk factors such as smoking, hypertension, diabetes, lack of physical activity, low levels of HDL (the "good" cholesterol) and high levels of LDL (the "bad" cholesterol), the researchers found that triglyceride was an independent risk factor for heart disease, even at lower levels. "It turns out from our study that people with triglyceride levels in the low 100s had about the same risk for heart disease as those with diabetes. In light of that, we may need to reevaluate current guidelines," says Dr. Miller. He adds that in the study, the risk did not go up with increasing levels of triglyceride. It remained a significant predictor of heart disease at 200 mg/dl, at 150 mg/dl, and at 100 mg/dl, the lowest level that the researchers evaluated. According to current guidelines by the National Cholesterol Education Program, a blood triglyceride level of less than 200 mg/dl is considered safe. Triglyceride is a type of fat that is always circulating in the blood, especially after a meal high in saturated fat. These fat particles are normally broken down by enzymes. When that process is not working efficiently, the triglycerides that are only partially broken down can cause fatty deposits in blood vessels, leading to atherosclerosis. Dr. Miller says we can enhance the breakdown of these fats by doing regular exercise, eating a diet low in saturated fat, and eating foods that are high in omega 3 fatty acids. Those include fresh fish, such as salmon, herring, mackerel, and sardines and tuna that is either fresh or packed in water, not in oil. Dr. Millers' co-authors were Azita Moalemi, M.D., Alexander Seidler, Ph.D., and Naghmeh Tebyanian, M.D., from the University of Maryland Medical Center and Thomas A. Pearson, M.D., Ph.D., from the Mary Imogene Bassett Hospital in Cooperstown, N.Y. Major Study of Surgery for Severe Emphysema to BeginThe University of Maryland Medical Center is one of 18 sites chosen by federal health officials to perform lung volume reduction surgery for people with severe emphysema who are covered by Medicare. The surgeries will be part of a seven-year, national study to evaluate the safety and efficacy of the procedure, which involves the removal of about 20 to 30 percent of a patient's over-inflated, diseased lungs. Physicians at the University of Maryland Medical Center and the Johns Hopkins University will collaborate to form the Maryland Lung Volume Reduction Surgery Clinical Center. Patients in the study will undergo evaluation and receive medical therapy at either the University of Maryland Medical Center or the Johns Hopkins Hospital, and those selected for surgery will have it performed at the University of Maryland. "This study will be important for us to evaluate definitively the role of lung volume reduction surgery and find out which patients would benefit most," says Mark Krasna, M.D., director of general thoracic surgery at the University of Maryland Medical Center. Dr. Krasna, an associate professor of surgery who is the principal investigator of the study in Maryland, has performed volume reduction surgery on more than 75 patients since 1994. Jonathan Orens, M.D., an assistant professor of medicine and pulmonologist at the University of Maryland and Henry Fessler, M.D., an assistant professor of medicine and pulmonologist at Johns Hopkins University School of Medicine, are working with Dr. Krasna on the study.
Pictured: Mark Krasna, M.D. The surgery is offered to patients with severe emphysema, a chronic condition that is a major cause of death and disability in the United States, affecting about two million Americans. Lung volume reduction surgery has helped many patients to have improved lung function and better quality of life because their lungs are more able to expand and contract. However, the surgery is risky since patients have decreased lung function and are quite ill before the surgery because of their emphysema. This will be the first large, prospective study of the surgical procedure. The study will be conducted by the National Heart, Lung, and Blood Institute (NHLBI) and funded by the Health Care Financing Administration (HCFA), which will cover patient care costs for the Medicare beneficiaries who are candidates in the study. It is the first time HCFA and NHLBI have collaborated on a study of this magnitude. Nationwide, about 2,600 patients will be enrolled. All will receive intensive medical therapy and pulmonary rehabilitation. Half of the patients will be randomly selected to undergo the volume reduction surgery. Throughout the study, all participants will be evaluated for exercise ability, lung function, quality of life, illness and survival. Both the University of Maryland and Johns Hopkins will evaluate and follow patients in the study and guide medical treatment. The University of Maryland Medical Center is the only site in the Mid-Atlantic region where surgery will be performed as part of the study. In addition, it is one of only six centers in the United States where the surgery will be performed in two different ways. One method involves a standard chest incision. The other approach, a less invasive technique called thoracoscopy, requires only a few small incisions and is guided by a video camera. Medical therapy for emphysema includes medications to dilate constricted airways, reduce inflammation, and prevent infection. Exercise training and supplemental oxygen are also used. -Ellen Beth Levitt |
The two-year, nationwide study of Copolymer 1 involved 251 patients.
Half received the drug and the other half took a placebo. Researchers
looked for the number of relapses, or attacks, among those in
the study as an important indicator of how well the drug was working.
The patients who took Copolymer 1 had a 32 percent lower relapse
rate than the placebo group. The drug also had a positive influence
on neurologic disability. Patients who took the drug had less
on-going disability, such as problems with mobility and vision,
between relapses and at the end of the study. In addition, there
were few side effects.
Insulin, taken daily by millions of diabetics, and immunoglobulins
used to treat immune system deficiencies, have to be injected
because they are macromolecules, too big to be absorbed through
the digestive system. A tangled network of cellular proteins called
tight junctions normally prevents all but the tiniest molecules
from passing through the cells of the intestinal walls into the
blood stream.
In the study, Dr. Miller and his colleagues followed 460 men and
women age 30 to 80 who had been evaluated for coronary artery
disease in 1977-78. They contacted them to see how many had experienced
a heart attack, had required a procedure to open up blocked heart
vessels, or had died from heart disease.
"While this operation has been performed on several thousand patients over the past two years, the duration of its benefit and its role in the comprehensive care of patients with emphysema can only be learned by direct comparison with the best available non-surgical care," says Dr. Fessler.
